Formula (I) below shows the structure of S-(−)-nicotine (NIC), which activates neuronal nicotinic receptors evoking release of dopamine (DA) from presynaptic terminals in the central nervous system (CNS). NIC is a legal substance of dependence that produces many of its effects on the CNS, some of which may be considered to be beneficial e.g., mood elevation, arousal and learning and memory enhancement. NIC produces its effect by binding to a family of ligand-gated ion channels, stimulation by acetylcholine (ACh) or NIC causes the ion channel to open, and cations to flux with a resulting rapid (in millisec) depolarization of the target cell.
Over the last 12 years, there has been a substantial increase in studies on brain nicotinic receptors. Adult peripheral nicotinic muscle receptors are composed of four subunit domains: 2α, β, γ and δ. Traditional peripheral nicotinic receptor antagonists are shown in formula (II) and (III), i.e. decylmethonium (DEC) (muscle), hexamethonium (HEX) (ganglionic), and d-tubocurarine (d-Tc) (muscle). These compounds have also shown the ability to weakly inhibit neuronal nicotinic receptors.
Neuronal nicotinic receptors are composed of only two subunits, α and β and are believed to assemble with the general stoichiometry of 2α and 3β. Nine subtypes of the α subunit (α2 to α10) and three subtypes of the β unit (β2 to β4) are found in CNS. The most common nicotinic receptor species in the brain is composed of two α4 and three β2 subunits, i.e., α4β2. These subunits display different, but overlapping, patterns of expression in the brain.
For the most part, the actual subunit compositions and stoichiometries of nicotinic receptors in the brain remain to be elucidated. Thus, neuronal nicotinic receptor subtype diversity originates from differences in the amino acid sequence at the subunit level and from the multiple combinations of assemblies of subunits, which can form functional receptor proteins.
In spite of the extensive diversity in neuronal nicotinic receptor messenger RNA expression, only a limited number of tools are available to study the pharmacology of native receptors. Radioligands are used in many such studies. [3H]NIC appears to label the same sites in the brain as [3H]ACh. It has been estimated that over 90% of [3H]NIC binding in the brain is due to association with the heteromeric receptor that is composed of α4 and β2 subunits. Also abundant in the CNS, are the receptors labeled by [3Hmethyllycaconitine (MLA), which has high affinity for the α7 homomeric nicotinic receptor subtype. Additionally, nicotinic receptor subtypes can be studied using functional assays such as NIC-evoked [3H]dopamine (DA) release from rat striatal slices. Nicotinic receptors are located on the cell body and terminals of the nigrostiatal pathway. NIC facilitates DA release from striatal nerve terminals. Studies strongly suggest that the [3H]DA release assay is useful to probe α3β2* nicotinic receptor subtypes.
Structural and functional diversity of CNS nicotinic receptors has stimulated a great deal of interest in developing novel, subtype-selective agonists. Some of these agonists are currently being evaluated in clinical trials for cognitive enhancement and neuroprotective effects potentially beneficial for disease states such as Alzheimer's and Parkinson's Disease. Surprisingly, little attention has been focused on developing subtype-selective antagonists for neuronal nicotinic receptors. Potential uses of nicotinic receptor anatagonists are for the treatment of psychostimulant abuse, smoking cessation, and schizophrenia.
A class of pyridino N-substituted nicotine analogs having formula (IV) below are known antagonists that have affinity in the [3H]NIC binding assay and demonstrate the ability to inhibit NIC-evoked [3H]DA release. The abbreviated nomenclature is given in parentheses.
These compounds are useful in the treatment of nicotine abuse, smoking cessation therapy, as an antidote for nicotine intoxication, treatment of cognitive disorders such as Alzheimer's disease and for the treatment of Parkinson's disease. These compounds and their method of use were the subject of U.S. Pat. No. 5,691,365, issued Nov. 25, 1997. The content of this patent is incorporated herein by reference.
The invention disclosed herein is directed to a series of efficacious and subtype-selective nicotinic antagonists at nicotinic receptors in the CNS. These compounds comprise alkenyl alkynyl, branched and cyclic pyridine-N substituted NIC analogs.